The adult respiratory distress syndrome (ARDS) is a form of acute respiratory failure (ARF) often associated with gram-negative sepsis and a mortality rate of 50% or higher. Recent observation suggest that toxic 02 metabolites and mobilization of arachidonic acid metabolites are intimately involved in the pathogenesis. Infusion of endotoxin into animals is considered an excellent model of ARDS because many features of the syndrome can be reproduced. We propose to examine the roles of lipoxygenase and cyclooxygenase products, and their interaction with toxic 02 metabolites, in the pathophysiology of endotoxin-induced ARF. These objectives will be accomplished by utilizing an isolated perfused porcine lung (IPPL) in addition to the in vivo animal model. The specific objectives are: 1) To determine the role of lipoxygenase products during endotoxemia in the intact and during endotoxin treatment of the IPPL preparation by specific blockade of the lipoxygenase pathway (BW A46) and LTD4/LTE4 receptors (LY171883), and by infusion of leukotrienes into isolated lungs. 2) To determine the role of cyclooxygenase products by specific blockade of cyclooxygenase (indomethacin) and thromboxane synthetase (dazoxiben) pathways, thromboxane A2 (TXA2) receptors (SQ 29,548), and by infusion of a TXA2 mimetic (U46619) into lungs pretreated with endotoxin and a cyclooxygenase inhibitor. 3) To determine the role of toxic 02 metabolites during endotoxemia and their interaction with eicosanoid biosynthesis in vivo and in the IPPL. This will be accomplished by treating intact and isolated pig lungs with scavengers of hydrogen peroxide (polyethylene glycol catalase and hydroxyl radical (dimethylthiourea). LTB4, LTC4/LTD4/LTE4, 12- HETE, and 15-HETE will be measured using reverse phase-high performance liquid chromatography ultraviolet spectroscopy, and radioimmunoassay. TXB2 and 6-keto-PGFI will also be measured by radioimmunoassay. Physiologic parameters to be measured or calculated include: pulmonary vascular and airway pressures, pulmonary vascular resistance, lung vascular endothelial and alveolar-capillary membrane permeability, lung water, PO2, PCO2, and alveolar dead-space ventilation. If increased levels of eicosanoids can be correlated with the presence of toxic 02 metabolites and abnormal cardiopulmonary function, then future studies will focus on identifying specific cellular mechanisms by which these metabolites contribute to lung injury.